Abstract 5263: Licochalcone A is a candidate for breast cancer prevention through its reprogramming of metabolic and antioxidant pathways
Authors: Atieh Hajirahimkhan, Elizabeth Bartom, Sriram Chandrasekaran, Xiaoling Xuei, Susan Clare, Seema Khan
Journal: Cancer Research (2023)

Abstract Background: Increased adiposity is a risk factor for postmenopausal breast cancer. It is accompanied by protumorigenic effects: chronic low-grade inflammation and elevated levels of reactive oxygen species. Breast cancer risk reducing drugs with proven efficacy have adverse side effects, significantly minimizing their uptake and impact. Effective alternative strategies with lower toxicity are needed. We have shown that licochalcone A (LicA) suppresses aromatase expression and activity, enhances the activity of detoxifying enzymes, and reduces estrogen genotoxic metabolism in cell lines and animal models. However, no previous data exist on the breast tissue of women at substantial risk of breast cancer. We hypothesize that LicA creates a tumor preventive environment in the breast by modulating antioxidant/anti-inflammatory responses in the breast and adipogenesis leading to decreased proliferation. Methods: We prepared microstructures from the fresh tissue of contralateral unaffected mastectomy specimens of 6 postmenopausal women with incident unilateral breast cancer. After exposing them to DMSO (control) and LicA (5 µM), we performed total RNA sequencing. Differentially expressed genes were identified, and analyzed by gene ontology and pathway membership. The RNA-seq data was utilized also to conduct metabolism flux analysis. Combined enrichment scores &amp;gt; 4 and FDR &amp;lt; 0.05 was considered significant. The NanoString metabolism panel was employed in 6 additional subjects. We performed live cell imaging to monitor proliferation of pre-malignant DCIS.COM, DCIS.COM/ER+ PR+; and malignant MDA-MB-231 (ER- PR-), MCF-7 (ER+ PR+), MCF-7aro, and BRCA1 defective HCC-1937, and HCC3153 cells. Results: We observed upregulation of antioxidant genes (up to 8-fold), consistent with upregulation of NRF2 and the thioredoxin system, the major regulators of antioxidant pathways. This was accompanied with the significant downregulation of RELA- and NF-kB1-dependent inflammatory pathways. In addition, we observed decreased expression of the pro-adipogenic transcription factors SREBF1 and SREBF2, which may explain the downregulation (4 to 32-fold) of cholesterol biosynthesis and transport, and lipid metabolism genes. Metabolism studies confirmed these data and demonstrated a robust increase in the pentose phosphate shunt and NAD(P)H generation without enhancing ribose 5 phosphate formation, suggesting an antioxidant and anti-proliferative environment. LicA also suppressed proliferation of pre-malignant and malignant cells, with sustained effects on aggressive cells at doses &amp;lt; 10 µM. Conclusion: Our data suggest that LicA is a good candidate for breast cancer prevention through modulation of metabolic and antioxidant pathways leading to decreased proliferation. Our ongoing in vivo study will further demonstrate the efficacy of LicA for breast cancer prevention. Citation Format: Atieh Hajirahimkhan, Elizabeth Bartom, Sriram Chandrasekaran, Xiaoling Xuei, Susan Clare, Seema Khan. Licochalcone A is a candidate for breast cancer prevention through its reprogramming of metabolic and antioxidant pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5263.